Palladium-Catalyzed Selective Amino- and Alkoxycarbonylation of Iodoarenes with Aliphatic Aminoalcohols as Heterobifunctional O,N-Nucleophiles

Palladium-catalyzed amino- and alkoxycarbonylation reactions of aryl iodides were investigated in the presence of aliphatic heterobifunctional N,O-nucleophiles. Selective synthesis of amide alcohols and amide esters was realized, controlled by the base and substrate ratio. The effect of iodobenzene substituents was also studied with surprising results in terms of product selectivity. In addition to the model ethanolamine/iodobenzene system, various heteroaromatic substrates and numerous related nucleophiles were tested under optimized conditions, providing moderate to good yields of the target compounds. Reactions of serinol and 1,3-diamino-2-propanol as model trifunctional compounds showed particularly high chemoselectivity on amide ester products. Considering the coordinative properties of the applied nucleophiles, a rational catalytic cycle was proposed.

2. Screening of the reaction conditions for carbonylation of iodobenzene and aminoethanol S2 3. Screening of the para-substituent effect and competitive reactions S3 4. General procedure of product isolation/purification S4 5. MS-data table of ring substituted amides (3b-f) and amide-esters (4b-f) S4 6. General procedure for the hydrolysis of amide-esters to amide-alcohols and carboxylic acids S4 7. Characterisation and spectroscopic data ( 1 H, 13 C, MS) of prepared compounds S5 8. 1 H, 13 C{ 1 H}, MS spectrum of the isolated compounds S11

Typical carbonylation experiments performed under atmospheric CO pressure a. for the synthesis of amide-alcohols
Catalyst precursor [Pd(OAc)2] (2 mol %, 2.25 mg) and triphenylphosphine (4 mol % , 5.24 mg), were placed in a three-necked flask and refilled with argon gas three times. DMF (10 mL), iodobenzene (0.5 mmol. 56 μL), ethanolamine (0.5 mmol, 30 μL) and Et3N (2.0 mmol, 278 μL) were transferred to the flask. The atmosphere was changed to carbon monoxide (1 bar). The mixture was heated with heat-on block system (100 °C ) and stirred with magnetic stirrer for 24 hours. After the reaction was completed, the mixture was cooled, filtered and immediately analysed by GC and GC-MS. GC yields were determined by using ethylparabene as external standard.

b. for the sysnthesis of amide-esters
Catalyst precursor [Pd(OAc)2] (2 mol %, 2.25 mg) and triphenylphosphine (4 mol % , 5.24 mg), were placed in a three-necked flask and refilled with argon gas three times. DMF (10 mL), iodobenzene (0.5 mmol. 56 μL), ethanolamine (1.0 mmol, 60 μL) and Cs2CO3 (2.0 mmol, 651.6 mg) were transferred to the flask. The atmosphere was changed to carbon monoxide (1 bar). The mixture was heated with heat-on block system (100 °C ) and stirred with magnetic stirrer for 24 hours. After the reaction was completed, the mixture was cooled, filtered and immediately analysed by GC and GC-MS. GC yields were determined by using ethylparabene as external standard.

Screening of the reaction conditions for carbonylation of iodobenzene and aminoethanol
For optimisation reactions, 12 places parallel reaction station was used. Experimental setting is detailed in the following tables. Stock solutions of unvaried ingredients were prepared and divided into the vessels, than varied reagents were measured separately to the vessels.

Table S1. Experimental setup of round I.
In vessel 10-12 dichloromethane was used as solvent to transfer the unvaried reagents (2-2 mL in each vessels). The solvent was then evaporated under vacuum and 2 mL of MeCN, NMP and GVL was added separately (to vessels 10-12, respectively). The atmosphere of the vessels was changed to carbon monoxide (1 bar) and reaction mixtures were heated with heat-on block system to 100 o C and stirred

S3
with magnetic stirrer for 24 hours. After the reactions were completed, the mixtures were cooled, filtered and immediately analysed by GC and GC-MS. GC yields were determined by using ethylparabene as external standard.

Table S2. Experimental setup of round II.
Stock solution of iodobenzene, aminoethanol, palladium(II) acetate and DMF was transferred to the vessels. Variable reagents (ligands and base) were measured separately directly to the vessels. Additional iodobenzene was measured into vessels 9-12 providing the substrate/nucleophile ratio 2:1. The atmosphere of the vessels was changed to carbon monoxide (1 bar) and reaction mixtures were heated with heat-on block system to 100 o C and stirred with magnetic stirrer for 24 hours. After the reactions were completed, the mixtures were cooled, filtered and immediately analysed by GC and GC-MS. GC yields were determined by using ethylparabene as external standard.

Screening of the para-substituent effect and competitive reactions
For these reactions, 12 places parallel reaction station was used. Experimental setting is detailed in the following table. Stock solution of unvaried ingredients was prepared and divided into the vessels, then varied reagents were measured separately to the vessels.

S4
In vessels 1-6 aminoethanol-substrate ratio was kept at 1:1. In experiments 7-12 aminoethanol substrate ratio was increased to 1:2 by adding 0.2 mmol of both substrates. The atmosphere of the vessels was changed to carbon monoxide (1 bar) and reaction mixtures were heated with heat-on block system to 100 o C and stirred with magnetic stirrer for 24 hours. After the reactions were completed, the mixtures were cooled, filtered and immediately analysed by GC and GC-MS. GC yields were determined by using ethylparabene as external standard.

General procedure of product isolation/purification
The reaction mixture was concentrated under vacuum and the crude product was purified by column chromatography on silica gel using chloroform/ethyl acetate eluent to afford the corresponding products. Table S4.

MS data of ring substituted derivatives
Mixed products cannot be isolated by chromatography.

General procedure for the hydrolysis of amide-esters to amide-alcohols and carboxylic acids
The crude reaction mixture (10 mL) of carbonylation reactions was evaporated under vacuum to remove DMF. The residue was dissolved in ethanol (4 mL) and deionized water (2 mL), then sodium hydroxide was added (~100 mg). The solution was heated with heat-on block system to 80 o C and stirred for 2 hours. After cooling down the solution with ice bath concentrated HCl was added to reach  (4), 163 (7), 144 (4).

Amide-Esters
179 ( S5 acidic pH. The solution was washed with diethyl ether (10 mL) two times and the organic phase was dried over anhydrous sodium sulphate. After filtration the solvent was evaporated and the product was analysed by GC-MS.